Keigo Yoshinaga

Depth of invasion parallels increased cyclooxygenase‐2 levels in patients with gastric carcinoma

Nonsteroidal anti‐inflammatory drugs may reduce the incidence of intestinal carcinoma, presumably through inhibition of cyclooxygenase‐2 (COX‐2). The authors correlated tumor expression of COX‐2 with clinicopathologic features in tissues from patients with gastric carcinoma.

Neurotensin Stimulates Growth of Colonic Mucosa in Young and Aged Rats

Neurotensin, a tridecapeptide widely distributed in the gut, stimulates growth of small bowel mucosa in young and aged rats. In the present study, the effect of long-term neurotensin administration on the growth of colonic mucosa was examined in young (2-month-old) and aged (24-month-old) rats. Subcutaneous injections of saline (control) or neurotensin (300 micrograms/kg) in gelatin were given to the groups of rats every 8 hours for 10 days. During treatment, all rats were maintained on a regular chow diet. Rats were killed on day 11; the entire colon was removed, mucosa was scraped and weighed, and DNA, RNA, and protein contents were determined. Neurotensin induced growth of colonic mucosa in both age groups. In young rats, neurotensin increased weight and DNA, RNA, and protein contents of colonic mucosa. The ratio of DNA content, an index of cellular hyperplasia, was increased significantly in the neurotensin-treated young rats compared with age-matched controls, indicating an overall increase in mucosal cellularity. In the aged rats, growth was characterized by an increase in weight and RNA and protein contents, but not DNA content, thus suggesting cellular hypertrophy. These results suggest that neurotensin has an important regulatory function in the growth of colonic mucosa; however, the mode of action, at the cellular level, appears to be different depending on age.

Discontinuous rectal cancer spread in the mesorectum and the optimal distal clearance margin in situ.

AbstractPURPOSE: We examined the frequency, mode, and extent of discontinuous spread of rectal cancer in the mesorectum to determine the optimal distal clearance margin in situ. METHODS: Forty consecutive patients with rectal cancer undergoing locally curative resection were studied prospectively. Discontinuous cancer spread in the mesorectum and the extent of distal spread was examined microscopically. A tissue shrinkage ratio comparing the distal clearance margin measured before transection to that measured after fixation in each case, was used to convert microscopically measured extent of distal spread to extent in situ. RESULTS: Discontinuous cancer spread in the mesorectum was observed in 17 cases (43 percent); lymph node metastasis in 15 cases (38 percent) and small deposits other than nodal metastases in 8 cases (20 percent). Distal cancer spread (either intramural or mesorectal) was observed in 6 cases (15 percent). The mean distal clearance margin before transection and after fixation was 3.2 cm and 2 cm, respectively. The mean tissue shrinkage ratio was 60 percent. The maximum extent of microscopic distal spread and adjusted distal spread in situ were 20 and 24 mm, respectively. CONCLUSIONS: Excising the mesorectum with fascia propria circumferentially intact is essential for rectal surgery. The optimal distal clearance margin for the rectal wall as well as the mesorectum in situ can be reduced to 3 cm with a right angle.

Neurotensin augments intestinal regeneration after small bowel resection in rats.

Massive small bowel resection (SBR) is characterized by increased proliferation of residual gut mucosa and pancreas. Neurotensin (NT), a gut tridecapeptide, stimulates growth of normal gut mucosa and pancreas. This study examined whether NT affected growth of the small intestine and the pancreas after either distal or proximal SBR. Male Fischer 344 rats were divided into four groups. Group 1 underwent ileal transection with reanastomosis (SHAM) and group 2 underwent 70% distal SBR. Group 3 underwent SHAM operation (jejunal transection), and group 4 underwent 70% proximal SBR. After operation, each group was further subdivided to receive either saline (control) or NT (300 micrograms/kg) subcutaneously in gelatin every 8 hours for 7 days. At death, the pancreas and proximal jejunum (from groups 1 and 2) or distal ileum (from groups 3 and 4) were removed, weighed, and analyzed for DNA, RNA, and protein content. Both proximal and distal SBR significantly increased mucosal growth in the remnant intestine; a more pronounced effect was noted with proximal SBR. Administration of NT significantly augmented the adaptive changes in both groups of rats by mechanisms involving increases in both cell size (hypertrophy) and cell number (hyperplasia). Pancreatic growth was stimulated by distal (but not proximal) SBR; NT did not augment this response. The authors conclude that NT augments intestinal growth after SBR by mechanisms involving an increase in overall mucosal cellularity. Administration of NT may be therapeutically useful to enhance mucosal regeneration during the early period of adaptive hyperplasia after SBR.

ABCC13, an unusual truncated ABC transporter, is highly expressed in fetal human liver.

In the present study, we have cloned the cDNA of ABCC13, a novel ABC transporter, from the cDNA library of adult human placenta. The ABCC13 gene spans approximately 70kb on human chromosome 21q11.2 and consists of 14 exons. The open reading frame of the ABCC13 cDNA encodes a peptide consisting of 325 amino acid residues. The amino acid sequence corresponding to putative membrane-spanning domains was remarkably similar to ABCC1, ABCC2, ABCC3, and ABCC6. The ABCC13 gene was expressed in the fetal liver at the highest level among the organs studied. While ABCC13 was expressed in the bone marrow, its expression in peripheral blood leukocytes of adult humans was much lower and no detectable levels were observed in differentiated hematopoietic cells. The expression of ABCC13 in K562 cells decreased during cell differentiation induced by TPA. These results suggest that the expression of human ABCC13 is related with hematopoiesis.

Expression of cyclooxygenase-2 (COX-2) mRNA in human colorectal adenomas

Cyclooxygenase-2 (COX-2) is an important target for the suppression of colorectal tumorigenesis by non-steroidal anti-inflammatory drugs (NSAIDs). To evaluate the role of COX-2 in human sporadic colorectal adenomas, COX-2 mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) in 63 adenomas. COX-2 mRNA was detected in all the adenomas at higher levels than in normal colorectal mucosa (P<0.001). Levels of expression in the adenomas were correlated with their size (P=0.019), but no relationships were demonstrable between COX-2 expression and adenoma location, macroscopically observed configuration or microscopic degree of dysplasia. These findings suggest that COX-2 plays an important role in the growth of sporadic colorectal adenomas.

Molecular evidence for multicentric development of thyroid carcinomas in patients with familial adenomatous polyposis.

Familial adenomatous polyposis is characterized by multiple colorectal adenomas and an increased incidence of colorectal carcinomas. Patients also develop various extracolonic tumors, of which, thyroid carcinoma is common in young females. The occurrence of multiple carcinomas in one thyroid is frequently observed, although some carcinomas are solitary. To clarify whether each carcinoma develops independently or metastatically spreads from the first one formed, we analyzed the adenomatous polyposis coli (APC) gene mutation in each carcinoma. We found that each carcinoma had a different somatic mutation of the APC gene. This is molecular confirmation for the multicentric development of thyroid carcinomas in familial adenomatous polyposis through biallelic inactivation of the APC gene.

Quantification of telomerase activity in sporadic colorectal carcinoma

Activation of telomerase, a ribonucleoprotein enzyme complex that synthesizes telomere repeats, is associated with acquisition of unlimited cellular proliferation and is commonly detected in human cancer. Measurement of telomerase activity (TA) may provide important information as a diagnostic marker or a prognostic indicator. The authors studied the quantification of TA and assessed its utility as a prognostic marker in sporadic colorectal carcinoma.

Cyclooxygenase-2 expression in colorectal adenomas.

AbstractPURPOSE: Cyclooxygenase-2 is an important target for nonsteroidal anti-inflammatory drugs in suppressing colorectal tumorigenesis. To evaluate the role of cyclooxygenase-2 in sporadic colorectal adenoma, we correlated cyclooxygenase-2 expression in adenomas with other adenoma characteristics. METHODS: Cyclooxygenase-2 expression was evaluated immunohistochemically in 95 endoscopically resected colorectal adenomas. RESULTS: Cyclooxygenase-2 was expressed mainly in the cytoplasm of adenoma cells, where it was seen in 74 percent (70/95) of adenomas. Expression was related significantly to grade of dysplasia (P < 0.001) and tumor size (P = 0.028). Multivariate logistic regression analysis showed cyclooxygenase-2 expression in adenoma cells to be independently associated with grade of dysplasia (P = 0.001). CONCLUSION: Observed associations suggest that cyclooxygenase-2 plays an important role in progression of the adenoma-to-carcinoma sequence.

Somatic Mutation of the APC Gene in Thyroid Carcinoma Associated with Familial Adenomatous Polyposis

We report the existence of both germline and somatic mutations of the APC gene in thyroid carcinomas from familial adenomatous polyposis (FAP) patients. One papillary thyroid carcinoma from a 20‐year‐old woman, with germline mutation of the APC gene (TCA to TGA at codon 1110), showed a somatic mutation of AAAAC deletion between codons 1060 and 1063. Another somatic mutation of CAG to TAG at codon 886 was also found in one of multiple thyroid carcinomas from a 26‐year‐old woman with attenuated FAP and germline mutation at codon 175 (C deletion). This is the first evidence that total absence of the normal function of the APC gene is involved in development of thyroid carcinomas in FAP.